Reproducibility of the whole-brain N-acetylaspartate level across institutions, MR scanners, and field strengths

Abstract

Background and purpose: Radiologic markers in multicenter trials are often confounded by different instrumentation used. Our goal was to estimate the variance of the global concentration of the neuronal cell marker N-acetylaspartate (NAA) among research centers using MR imaging scanners of different models, from different manufacturers, and of different magnetic field strength.

Materials and methods: Absolute millimolar amounts of whole-brain NAA (WBNAA) were quantified with nonlocalizing proton MR spectroscopy in the brains of 101 healthy subjects (53 women, 48 men) aged 16-59 years (mean, 34.2 years). Twenty-three were scanned at 1 institute in a 1.5T Siemens Vision; 31 from another institute were studied with a 1.5T Siemens SP63; 36 were scanned at a third institute (24 with a 1.5T Vision, 12 with a 3T Siemens Trio); and 11 were obtained at a fourth institute using a 4T GE Signa 5.x. The NAA amounts were quantified with phantom-replacement and divided by the brain volume, segmented from MR imaging, to yield the concentration, a metric independent of brain size suitable for cross-sectional comparison.

Results: The average WBNAA concentration among institutions was 12.2 +/- 1.2 mmol/L. The subjects' WBNAA distributions did not differ significantly (p > .237) among the 4 centers, regardless of scanner manufacturer, model, or field strength and irrespective of whether adjustments were made for age or sex.

Conclusion: Absolute quantification against a standard makes the WBNAA concentration insensitive to the MR hardware used to acquire it. This important attribute renders it a robust surrogate marker for multicenter neurologic trials.

Fig 1.

Sample whole-head ¹H-MR spectroscopy spectra from each of the MR imaging instruments used, with institution and field strength indicated. Although all the proton metabolites can be seen in the spectrum, note that because it was acquired in a whole-head, nonlocalized fashion, only the NAA peak is implicitly localized to the brain. The area of the NAA peak of the subject S_S, was integrated in each subject as shown and converted into absolute millimoles, Q_NAA, by comparing with the NAA peak area, S_R, in a reference phantom of known concentration as described by Eq. 1. Note the excellent signal-to-noise ratio of this short acquisition and the nearly total elimination of the skull’s lipid signals from obscuring the spectrum.

Fig 2.

Box plot showing the 25%, 50% (median), and 75% quartiles (box) and ±95% (whiskers), of the distributions of the subjects’ WBNAA concentrations in each of the 4 institutions, 5 scanners, 3 field strengths, and 2 manufacturers used in this study. Note that the differences among the distributions (means and SDs) are statistically insignificant, independent of the (healthy) subjects’ age or sex, indicating that the methodology is robust to instrumentation differences.